1. Field of the Invention
This invention relates to a method of treating peptic ulcer disease in mammalian hosts by administering a substituted 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one compound.
2. Description of the Prior Art
The recent successful introduction of the histamine H.sub.2 -receptor antagonist, cimetidine, for the treatment of peptic ulcer disease has renewed interest in developing new antiulcer compounds which might have even greater potency and specificity and/or reduced side effects. The literature indicates significant progress in developing improved inhibitors of gastric acid secretion which work as H.sub.2 -receptor antagonists (e.g. ranitidine and etintidine) or by mechanisms other than competitive H.sub.2 -receptor antagonism. Another interesting approach to antiulcer therapy involves the search for so-called cytoprotective agents which have the property of protecting the gastrointestinal tract from damage induced by noxious agents. To date, the main studies of this cytoprotective effect have been carried out with prostaglandins, although a recent U.K. Patent Application No. 2,063,862A claims that the non-prostaglandin compound 5,6,7,8-tetrahydro-N-(5-tetrazolyl)-4-oxo-4H-pyrimido[2,1-b]benzothiazole- 3-carboxamide also has been found to possess cytoprotective effects. The term "cytoprotective" has been defined by A. Robert (Gastroenterology 77: 433-443, 1979; Advances in Prostaglandin and Thromboxane Research 2: 507, 1976; Scand. J. Gastroent. 16: 223-227, 1981) as the property of a compound to protect the mucosa of the stomach and intestine from becoming inflamed and necrotic when this mucosa is exposed to noxious agents. While the mechanism of cytoprotection is not yet known, cytoprotective effects by definition are independent of any antisecretory activity that a compound may also possess.
The substituted 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one compounds of the present invention have been previously disclosed in U.S. Pat. Nos. 4,122,274 and 4,209,620 as having antiallergery activity. There is no disclosure in these patents, however, that these compounds also have potent antiulcer activity.
With respect to other literature relating to the compounds of the present invention, no examples of tetrazol-5-yl-4H-pyrido[1,2-a]pyrimidin-4-ones have been located by the present inventors. Numerous examples of the pyrido[1,2-a]pyrimidine ring system, however, are known, including many 4-oxo derivatives.
U.S. Pat. No. 3,585,198 reviews some of the literature of the pyrido[1,2-a]pyrimidines and discloses compounds of the general formula ##STR1## where R, R.sup.1, R.sup.2 and R.sup.3 may be hydrogen, alkyl, alkoxy, halogen, nitro or amino, R.sup.4 is hydrogen, alkyl, aralkyl, aryl, .dbd.O, alkoxy, halogen or hydroxy, R.sup.5 is hydrogen, halogen, a --CH.sub.2 --OH group, a carboxylic acid or carboxylic acid derivative group, R.sup.6 is hydrogen, alkyl, aralkyl, aryl, .dbd.O, alkoxy, halogen, or hydroxy and R.sup.7 is hydrogen, alkyl, aryl or alkyl, and where the dotted lines represent optional double bonds. The disclosed compounds are said to exhibit analgesic, antipyretic and narcosis potentiating effects.
U.S. Pat. No. 3,929,787 discloses 2-aryl-9-alkyl-4H-pyrido[1,2-a]pyrimidin-4-one compounds of the formula ##STR2## where R.sup.1 is phenyl or substituted phenyl, R.sup.2 is hydrogen or alkyl and R.sup.3 is alkyl. These compounds are reported to be intermediates in preparing the corresponding 6,7,8,9-tetrahydro derivatives which possess central nervous system depressant activity.
U.S. Pat. No. 3,072,485 discloses inter alia compounds of the formula ##STR3## where R is hydrogen, bromo, chloro, iodo or methyl. The compounds are used as photogenic sensitizers.
Compounds of the formula ##STR4## wherein R is hydrogen, 9-methyl or 8-methyl are disclosed by Okamoto, et al. in Chem. Pharm. Bull. (Tokyo), 22, 243 (1974). No pharmacological utility for the compounds is indicated.
U.S. Pat. No. 3,960,847 discloses inter alia 9-substituted pyrido[1,2-a]pyrimidines of the formula ##STR5## where R.sup.1 is hydrogen or C.sub.1 -C.sub.4 alkyl, R.sup.2 and R.sup.3 are hydrogen, C.sub.1 -C.sub.4 alkyl, CF.sub.3, F, Cl or Br and R.sup.4 is inter alia an alkyl radical substituted by a phenyl or substituted phenyl radical, such as benzyl, substituted benzyl, phenethyl or substituted phenethyl. The compounds are said to have both central nervous system and hypotensive activities.
J. K. Landquist has described in J. Chem. Soc.(C), 2735 (1971) the preparation of the carboxamide compound of the formula ##STR6## by treatment of the corresponding ethyl ester with ammonium hydroxide in ethanol. No pharmacological utility is given for the disclosed carboxamide.
Preparation of the cyano derivatives of the formula ##STR7## where R is hydrogen, 6-methyl or 9-methyl is disclosed in J. Amer. Chem. Soc. 80: 3066 (1958). No pharmacological utility for the compounds is indicated.
Other references to the chemistry of pyrido[1,2-a]pyrimidinones include J. Amer. Chem. Soc. 74: 5491 (1952), J. Org. Chem. 33: 3015 (1968), Arzneim-Forsch. 22: 815 (1972) and Tetrahedron Lett. (12): 1019 (1975).
A number of structurally unrelated heterocycle compounds have been disclosed as having antiallergy and/or antiulcer activity. Representative of literature references disclosing such compounds are the following.
1. U.S. Pat. No. 4,310,526 discloses substituted 6,7-methylene pyrido[1,2-a]pyrimidines of the formula ##STR8## wherein A completes a bond, thereby providing a double bond between the 6- and 7-carbon atoms, or A represents a --CH.sub.2 -- group, thereby providing a cyclopropane ring fused to the pyrido ring at the 6,7-position; PA0 R.sub.1 represents a hydrogen atom or a C.sub.1 -C.sub.12 alkyl group which is unsubstituted or substituted by a ##STR9## group, wherein each of R.sub.4 and R.sub.5 independently represents a hydrogen atom or a C.sub.1 -C.sub.10 alkyl group, or R.sub.4 and R.sub.5, taken together with the nitrogen atom to which they are attached, form a N-pyrrolidinyl, piperidino or morpholino group; R.sub.2 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group or a C.sub.3 -- or C.sub.4 --alkenyl group; R.sub.3 represents (a) a furyl, thienyl or pyridyl group each of which is unsubstituted or substituted by a methyl group; or (b) a group of the formula ##STR10## wherein each of R.sub.6, R.sub.7 and R.sub.8 independently represents a hydrogen or halogen atom, a hydroxy group, a C.sub.1 -C.sub.4 dialkylamino group, a group --CF.sub.3 or a group --R.sub.9 or --OR.sub.9, where R.sub.9 represents a C.sub.1 -C.sub.6 alkyl or C.sub.3 -- or C.sub.4 --alkenyl group, and pharmaceutically acceptable salts thereof as having anti-allergic, anti-ulcer and anti-diabetic activities. PA0 2. U.K. Patent Application No. 2,063,862A discloses antiallergic and antiulcer 1-oxo-1H-thiazolo[3,2-a]-pyrimidine-2-carboxamides of the formula ##STR11## and their pharmaceutically acceptable salts, wherein R.sub.1 and R.sub.2 taken separately are each hydrogen or C.sub.1-5 alkyl; and R.sub.1 and R.sub.2 taken together are alkylene of 3-9 carbon atoms or phenylalkylene of 9-11 carbon atoms, with the proviso that the ring so formed is between 5- and 8-membered. PA0 3. U.S. Pat. No. 3,855,216 discloses substituted pyrano[3,2-c]-[1,2]benzothiazine 6,6-dioxides of the formula ##STR12## wherein R represents hydrogen and (lower)alkyl and R.sup.1 represents (lower) alkyl, formyl and hydroxymethyl and the corresponding aldehyde thiosemicarbazone derivatives thereof as having antisecretory and antiallergy activity. PA0 4. U.S. Pat. No. 3,862,141 discloses 1-substituted 1,2,3,4-tetrahydroxanthen-9-one compounds of the formula ##STR13## wherein X is hydroxy or carbonyl oxygen, R.sub.1 and R.sub.2 are hydrogen, halogen, (lower)alkyl, (lower)alkoxy or hydroxy, or R.sub.1 and R.sub.2 taken together form another ring such as benzene, as antisecretory and antiallergy agents. PA0 5. U.S. Pat. No. 4,014,881 discloses 1-oxo-1H-6-substituted pyrimido[1,2-a]quinoline-2-carboxylic acid derivatives of the formula ##STR14## wherein R.sub.1 is C.sub.1 -C.sub.2 alkoxy or piperidino and R.sub.2 is hydrogen or C.sub.1 -C.sub.4 alkyl and pharmaceutically acceptable salts as antiulcer agents. PA0 6. U.S. Pat. No. 4,041,163 discloses N-(5-tetrazolyl)-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamides of the formula ##STR15## wherein R.sup.1 is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxy, chloro, fluoro, trifluoromethyl, nitro, amino or methylthio and R.sup.2 is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxy, chloro, fluoro or methylthio, or R.sub.1 and R.sub.2 when taken together are methylenedioxy or ethylenedioxy, and pharmaceutically acceptable salts thereof as antiallergy agents. PA0 7. U.S. Pat. No. 4,236,004 discloses 2-alkylsulfonyl-7,8-dihydro-5-hydroxy-7-oxo-pyrido[2,3-d]pyrimidine-6-carb oxylic acid compounds of the formula ##STR16## wherein R.sup.2 is hydrogen, hydroxy, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkylthio, phenyl, 4-methoxyphenyl, 4-chlorophenyl, 1-pyrrolidinyl or methylphenylamino; R.sup.5 is hydroxy, C.sub.1 -C.sub.6 alkylamino, 2-hydroxyethylamino, 2-alkoxyethylamino of 3-8 carbons, dialkylamino where each alkyl is C.sub.1 -C.sub.6, 4-methyl-1-piperazinyl, 4-morpholinyl or 1-pyrrolidinyl when R.sup.2 is other than alkylthio and R.sup.8 is other than alkyl or -NH.sub.2 when R.sup.8 is other than alkyl; R.sup.6 is C.sub.1 -C.sub.6 alkoxy, amino, mono- and dialkylamino where each alkyl group is C.sub.1 -C.sub.6, 2-hydroxyethylamino, 2-alkoxyethylamino of 3-8 carbons or 2-(dialkylamino)ethylamino in which each alkyl group is C.sub.1 -C.sub.6 ; and R.sup.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, 2-alkoxyethyl of 3-8 carbons, allyl, propargyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)phenyl or piperonyl as having anti-secretory and antiallergy activity. PA0 8. U.S. Pat. No. 4,141,979 discloses tetrazolo[a]quinazol-5-ones of the formula ##STR17## wherein each of R.sup.1 and R.sup.2 is selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkanoyloxy, benzyloxy, hydroxy, trifluoromethyl, sulfonamido and halo, or R.sup.1 and R.sup.2 when taken together are methylenedioxy or ethylenedioxy, as antiallergy agents and as antiulcer agents. PA0 9. U.S. Pat. No. 4,105,766 discloses certain carboxylic acids and esters of the formula ##STR18## wherein R.sub.1 is hydrogen, lower alkyl or pivaloyloxymethyl; R.sub.2 is hydrogen, methyl, ethyl, lower-alkenyl or cyclopropylmethyl; and R.sub.3 is hydrogen, 7- or 8-methyl, 7- or 8-halo or 7-nitro as having antiallergy activity. This same patent, however, (and also U.S. Pat. No. 4,105,764) discloses that the above compounds have no antiulcer (antisecretory) activity whereas the corresponding compounds having an amide group at the 3-position have antiulcer activity but not antiallergy activity. PA0 (a) Halogen includes chlorine, bromine, fluorine and iodine, and is most preferably chlorine; PA0 (b) Lower(alkyl) includes both straight and branched chain saturated aliphatic hydrocarbon radicals having from 1-4 carbon atoms inclusive, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and sec-butyl, and is more preferably methyl, ethyl, n-propyl or n-butyl, and most preferably methyl, ethyl or n-propyl; and EQU (c) (CH.sub.2).sub.n PA0 represents a saturated five, six or seven membered monocyclic hydrocarbon radical fused to the A ring of the pyrido[1,2-a]pyrimidine ring system, e.g. ##STR20##